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Maturity-onset diabetes of the young (MODY) is a monogenic disorder of glucose homeostasis with several subtypes, each defined by a distinct genetic etiology. Heterozygous pathogenic variants in the insulin gene are rare causes of MODY, and optimal treatment strategies remain uncertain. Herein we describe a patient with diabetes caused by the heterozygous pathogenic variant R46Q in the insulin gene and the glycemic response to selected antidiabetic treatment regimens. The R46Q pathogenic variant leads to secretion of both mutant and wild-type insulin. In vitro, the mutant insulin is associated with a lower insulin-receptor affinity compared with wild-type insulin and a decline in wild-type insulin secretion. In our patient, treatment with a combination of long- and short-acting insulin led to a decline in hemoglobin A1C (HbA1c), although not to the recommended target. A shift to metformin and subsequent add-on of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) resulted in HbA1c levels of less than 7% (53 mmol/mol) and durable glycemic control. Continuous glucose monitoring and oral glucose tolerance tests confirmed that treatment with metformin and SGLT2i was superior to treatment with insulin. In conclusion, diabetes caused by the pathogenic variant R46Q in the insulin gene may be effectively treated with noninsulin.
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BACKGROUND: Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes. METHODS: The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text. RESULTS: There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU's effectiveness in lowering HbA1c. Two cross-over trials (each with 15-16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes. CONCLUSION: There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.
Monogenic diabetes is a type of diabetes caused by changes in genes that affect how the body makes or responds to insulin. Precision medicine (where knowledge of the gene change directs the selection of treatment) is available for some forms of monogenic diabetes. This study evaluated the published literature for several forms of monogenic diabetes to assess the level of evidence supporting specific precision treatments. Among the 146 small studies that we reviewed, only six compared different treatments. However, we found evidence supporting oral medications for some types of monogenic diabetes, and evidence that treatment is not needed for one particular type. Based on our results, we provide treatment recommendations for certain forms of monogenic diabetes and identify future directions for research to help us optimize precision medicine in monogenic diabetes.
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BACKGROUND: The appetite-suppressing potential of liver-expressed antimicrobial peptide 2 (LEAP2), and its antagonistic effects on the hunger-inducing hormone ghrelin have attracted scientific interest. It is unclear how LEAP2 is influenced by fasting and how it responds to specific nutrients. OBJECTIVES: The purpose of this investigation was to assess whether LEAP2 concentration 1) decreases after fasting, 2) increases postprandially, and 3) is regulated by nutrient sensing in the splanchnic bed. METHODS: Plasma LEAP2 concentration was measured in blood samples from 5 clinical cross-over trials, following 1) 36 h of fasting (n = 8), 2) 10 h of fasting (n = 37, baseline data pooled from 4 of the clinical trials), 3) Oral and intravenous glucose administration (n = 11), 4) Oral and intravenous Na-lactate administration (n = 10), and 5) Oral and intravenous Na-ß-hydroxybutyrate (BHB) administration (n = 8). All 5 trials included healthy males. RESULTS: Compared with a 10-h fasting period, the median LEAP2 concentration was 38% lower following 36 h of fasting (P < 0.001). Oral administration of glucose elevated, whereas intravenous glucose administration lowered LEAP2 concentration (intervention x time, P = 0.001), resulting in a mean difference of 9 ng/mL (95% confidence interval [CI]: 1, 17) after 120 min. Oral lactate increased, and intravenous lactate decreased LEAP2 (intervention x time, P = 0.007), with a mean difference between interventions of 10 ng/mL (95% CI: 6, 15) after 120 min. In contrast, oral and intravenous administration of BHB reduced the LEAP2 concentration (main effect of time, P < 0.001). CONCLUSIONS: Our investigations show that LEAP2 concentration was lower after a 36-h fast than an overnight fast and that oral delivery of glucose and lactate elevated LEAP2 concentration compared with intravenous administration, whereas LEAP2 concentrations decreased with both oral and intravenous BHB. This indicates that the LEAP2 concentration is sensitive to intestinal exposure to specific substrates, highlighting the need for future studies exploring the relationship between nutrients and LEAP2. This trial was registered at clinicaltrials.gov as NCT01840098, NCT03204877, NCT04299815, NCT03935841, and NCT01705782.
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Glucose , Ácido Láctico , Humanos , Masculino , Ácido 3-Hidroxibutírico , Jejum , Grelina , FomeRESUMO
Background: Beta-cell monogenic forms of diabetes are the area of diabetes care with the strongest support for precision medicine. We reviewed treatment of hyperglycemia in GCK-related hyperglycemia, HNF1A-HNF4A- and HNF1B-diabetes, Mitochondrial diabetes (MD) due to m.3243A>G variant, 6q24-transient neonatal diabetes (TND) and SLC19A2-diabetes. Methods: Systematic reviews with data from PubMed, MEDLINE and Embase were performed for the different subtypes. Individual and group level data was extracted for glycemic outcomes in individuals with genetically confirmed monogenic diabetes. Results: 147 studies met inclusion criteria with only six experimental studies and the rest being single case reports or cohort studies. Most studies had moderate or serious risk of bias.For GCK-related hyperglycemia, six studies (N=35) showed no deterioration in HbA1c on discontinuing glucose lowering therapy. A randomized trial (n=18 per group) showed that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes, and cohort and case studies supported SU effectiveness in lowering HbA1c. Two crossover trials (n=15 and n=16) suggested glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes was limited. While some patients with HNF1B-diabetes (n=301) and MD (n=250) were treated with oral agents, most were on insulin. There was some support for the use of oral agents after relapse in 6q24-TND, and for thiamine improving glycemic control and reducing insulin requirement in SLC19A2-diabetes (less than half achieved insulin-independency). Conclusion: There is limited evidence to guide the treatment in monogenic diabetes with most studies being non-randomized and small. The data supports: no treatment in GCK-related hyperglycemia; SU for HNF1A-diabetes. Further evidence is needed to examine the optimum treatment in monogenic subtypes.
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The use of the sleep-promoting hormone melatonin is rapidly increasing as an assumed safe sleep aid. During the last decade, accumulating observations suggest that melatonin affects glucose homeostasis, but the precise role remains to be defined. We investigated the metabolic effects of long-term melatonin treatment in patients with type 2 diabetes including determinations of insulin sensitivity and glucose-stimulated insulin secretion. We used a double-blinded, randomized, placebo-controlled, crossover design. Seventeen male participants with type 2 diabetes completed (1) 3 months of daily melatonin treatment (10 mg) 1 h before bedtime (M) and (2) 3 months of placebo treatment 1 h before bedtime (P). At the end of each treatment period, insulin secretion was assessed by an intravenous glucose tolerance test (0.3 g/kg) (IVGTT) and insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp (insulin infusion rate 1.5 mU/kg/min) (primary endpoints). Insulin sensitivity decreased after melatonin (3.6 [2.9-4.4] vs. 4.1 [3.2-5.2] mg/(kg × min), p = .016). During the IVGTT, the second-phase insulin response was increased after melatonin (p = .03). In conclusion, melatonin treatment of male patients with type 2 diabetes for 3 months decreased insulin sensitivity by 12%. Clinical use of melatonin treatment in dosages of 10 mg should be reserved for conditions where the benefits will outweigh the potential negative impact on insulin sensitivity.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Melatonina , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Glucose , Humanos , Insulina/metabolismo , Masculino , Melatonina/uso terapêuticoRESUMO
Context: Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive. Objective: Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism. Methods: We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status. Results: A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (Pâ =â .004) and RbG studies (Pâ =â .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (Pâ =â .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels. Conclusion: Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.
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OBJECTIVES: The glycated haemoglobin fraction A1c (HbA1c) is widely used in the management of diabetes mellitus, and the Siemens DCA Vantage™ point-of-care testing (POCT) instrument offers rapid HbA1c results even far from a clinical laboratory. However, the analytical performance has been questioned, and not much is known about effects of changing reagent lot, instrument and operator. We therefore compared the analytical performance of the DCA Vantage™ with established routine methods (Tosoh G8/G11 ion exchange HPLC) in a true clinical setting at two Danish hospitals. METHODS: We extracted all routine clinical HbA1c results incidentally drawn from the same patient within 48 h (n=960 pairs) and evaluated the effect of reagent lot, operator and instrument. We also performed a prospective method comparison in our diabetes out-patient clinic (n=97). RESULTS: The critical difference (CD) between two POCT results varied between 5.14 and 6.61 mmol/mol (0.47-0.55%), and the analytical imprecision of the DCA Vantage™ (CVA) was >3%. Significant effect of reagent lot and inter-instrument differences were found, whereas no effect of operator was seen. CONCLUSIONS: The DCA Vantage™ HbA1c analysis does not fulfil the prevailing analytical performance specifications, but rigorous validation of new reagent lots and continuous recalibration of instruments may potentially improve the precision substantially. Our findings, therefore, clearly emphasise the necessity of a close collaboration between clinicians and laboratory professionals in the POCT field. Finally, POCT HbA1c results should always be interpreted together with other measures of glycaemic control to avoid inappropriate change of patient treatments due to measurement uncertainty.
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Diabetes Mellitus , Sistemas Automatizados de Assistência Junto ao Leito , Diabetes Mellitus/diagnóstico , Hemoglobinas Glicadas/análise , Humanos , Testes Imediatos , Reprodutibilidade dos TestesRESUMO
NEW FINDINGS: What is the central question of this study? Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model? What is the main finding and its importance? The logistical set-up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1-13 C]lactate to [1-13 C]pyruvate, [1-13 C]alanine to [1-13 C]pyruvate, and 13 C-bicarbonate to [1-13 C]pyruvate, implying that the hyperpolarization technique might not be optimal for detecting effects of insulin in skeletal muscle of anaesthetized animals, which is of significance for future studies. ABSTRACT: In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1-13 C]pyruvate injection and hMR at baseline and after intervention. The glucose infusion rate per kilogram increased by a statistically significant amount in the HE and HH groups (P < 0.001). Hyperpolarized magnetic resonance showed no statistically significant changes in metabolite ratios: [1-13 C]lactate to [1-13 C]pyruvate in the HH group versus control group (P = 0.19); and 13 C-bicarbonate to [1-13 C]pyruvate ratio in the HE group versus the control group (P = 0.12). We found evidence of profound increments in glucose infusion rates representing skeletal muscle glucose uptake, but interestingly, no signs of significant changes in aerobic and anaerobic metabolism using hMR. These results imply that hyperpolarized [1-13 C]pyruvate might not be optimally suited to detect effects of insulin in anaesthetized resting skeletal muscle, which is of significance for future studies.
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Hipoglicemiantes , Ácido Pirúvico , Animais , Técnica Clamp de Glucose , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Modelos Animais , Músculo Esquelético/metabolismo , Ácido Pirúvico/metabolismo , SuínosRESUMO
BACKGROUND: Melatonin is increasingly used as a pharmacological sleep aid but it is also emerging as a regulator of glucose homoeostasis. Yet, previous research has been ambiguous with reports of both positive and negative effects of melatonin on glucose metabolism. OBJECTIVES: To assess the effect of daily treatment with melatonin on fasting glucose, insulin, insulin sensitivity and haemoglobin A1c (HbA1c) levels. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov and clinicaltrialsregister.eu were systematically searched. ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: All randomized, placebo-controlled studies with melatonin treatment were assessed. We included studies with daily melatonin treatment (≥2 weeks) of healthy adults or patients with metabolic diseases. METHODS: Hedges' g differences were calculated for the metabolic parameters of the included studies, heterogeneity was assessed with χ2 and I2 tests and meta-analyses were performed with the random-effects model. RESULTS: Long-term treatment with melatonin did not change fasting glucose significantly compared with placebo (g: -0.07 [-0.22 to 0.08], n = 603) but it reduced fasting insulin levels slightly (g: -0.27 [-0.50 to -0.04], n = 278) and trended towards reduced insulin resistance (HOMA-IR) (g: -0.20 [-0.44 to 0.03], n = 278). HbA1c levels were largely unaffected by melatonin treatment compared with placebo (g: 0.14 [-0.19 to 0.46], n = 142). CONCLUSIONS: With the available literature, melatonin seems to be a glucose-metabolic safe sleep aid in patients with metabolic diseases and in healthy adults. It may even have beneficial glucose-metabolic effects as fasting insulin levels were reduced in this meta-analysis, but the confidence intervals of the meta-analyses are wide, underscoring the need for further research within this field.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Melatonina , Adulto , Glicemia , Jejum , Glucose , Hemoglobinas Glicadas/análise , Humanos , InsulinaRESUMO
CONTEXT: Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms, with several lines of evidence suggesting that melatonin affects glucose homeostasis. OBJECTIVE: To evaluate the acute in vivo and in situ effects of melatonin on secretion of the incretin hormones, glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and their impact on ß-cell insulin secretion. DESIGN: A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in situ study of perfused rat intestines. SETTING: Aarhus University Hospital. METHODS: Fifteen healthy male participants were examined 2â ×â 2 times: an oral glucose tolerance test (OGTT) was performed on day 1 and an isoglycemic IV glucose infusion replicating the blood glucose profile of the OGTT day was performed on day 2. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in situ study, 6 rat intestines and 4 rat pancreases were perfused arterially with perfusion bufferâ ±â melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. RESULTS: In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA Pâ =â 0.003), an effect also observed in the perfused rat intestines (ANOVA Pâ =â 0.003), in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA Pâ <â 0.001). Despite a decrease in GIP levels, the in vivo glucose-stimulated insulin secretion was unaffected by melatonin (Pâ =â 0.78). CONCLUSION: Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in situ model of the rat intestine.
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Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Incretinas/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Intestinos/metabolismo , Melatonina/farmacologia , Adulto , Animais , Antioxidantes/farmacologia , Glicemia/análise , Estudos Cross-Over , Método Duplo-Cego , Seguimentos , Teste de Tolerância a Glucose , Voluntários Saudáveis , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Adulto JovemRESUMO
BACKGROUND: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years, it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights into both the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can be found in patients with diabetes diagnosed outside the first year of life. SCOPE OF REVIEW: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes. MAJOR CONCLUSIONS: The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein, usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast, recessive INS gene mutations typically result in no functional protein being produced due to reduced insulin biosynthesis or loss-of-function mutations in the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and within patients with identical mutations.
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Diabetes Mellitus/genética , Células Secretoras de Insulina/patologia , Insulina/genética , Idade de Início , Criança , Pré-Escolar , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático/genética , História do Século XXI , Humanos , Lactente , Recém-Nascido , Padrões de Herança , Insulina/história , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , MutaçãoRESUMO
BACKGROUND: Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. METHODS: 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. RESULTS: Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. CONCLUSIONS: We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.
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Diabetes Mellitus Tipo 2/microbiologia , Etnicidade , Microbioma Gastrointestinal , Adulto , Idoso , Dinamarca , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Índia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , FilogeniaRESUMO
Melatonin regulates circadian rhythm, but may also have effects on glucose homeostasis. A common G-allele in the MTNR1B locus has been associated with an increased risk of type 2 diabetes (T2DM). We aimed to examine acute effects of high doses of melatonin on glucose metabolism with attention to MTNR1B genotype. Twenty men were examined in a double-blinded, randomized crossover study on two nonconsecutive days with four doses of 10 mg oral melatonin or placebo. Insulin sensitivity and insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and a hyperinsulinaemic-euglycaemic clamp (HEC). Blood samples were drawn to determine the metabolic profile and MTNR1B rs10830963 genotype. Indirect calorimetry and blood pressure measurements were also performed. Insulin sensitivity index was significantly reduced on the melatonin day (P = .028) in the whole group and in homozygous carriers of the rs10830963 C-allele (P = .041). Glucose during the IVGTT was unaffected, but there was a tendency towards lower insulin and C-peptide levels in the first minutes after glucose administration in G-allele carriers. Systolic blood pressure decreased and lipid oxidation increased significantly on the melatonin day in rs10830963 G-allele carriers. Overall, our study reports that acute administration of melatonin in supra-physiological doses may have a negative impact on insulin sensitivity. Clinical trial registration number (clinicaltrial.gov): NCT03204877.
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Insulina/metabolismo , Melatonina/uso terapêutico , Receptores de Melatonina/metabolismo , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Calorimetria Indireta , Criança , Pré-Escolar , Estudos Cross-Over , Humanos , Resistência à Insulina/fisiologia , Peroxidação de Lipídeos/fisiologia , Masculino , Adulto JovemRESUMO
AIMS: Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counter-regulatory responses to hypoglycemia. Our study was designed to test whether (1) the metabolic responses and insulin sensitivity are impaired, and (2) whether they are affected by short-lived antecedent hypoglycemia in participants with T1D. MATERIALS AND METHODS: In a randomized, crossover, 2x2 factorial design, 9 male participants with T1D and 9 comparable control participants underwent 30 minutes of hypoglycemia (p-glucose < 2.9 mmol/L) followed by a euglycemic clamp on 2 separate interventions: with and without 30 minutes of hypoglycemia the day before the study day. RESULTS: During both interventions insulin sensitivity was consistently lower, while counter-regulatory hormones were reduced, with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5- to 10-fold increased ketone body concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake, and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue phosphatase and tensin homolog (PTEN) content, hormone-sensitive lipase (HSL) phosphorylation, and muscle glucose transporter type 4 (GLUT4) content were decreased compared with controls. And antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. CONCLUSIONS: Participants with T1D displayed insulin resistance and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact and ketogenic responses were amplified. We observed subtle alterations of intracellular signaling and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Insulina/efeitos adversos , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Dinamarca , Diabetes Mellitus Tipo 1/patologia , Técnica Clamp de Glucose/métodos , Humanos , Insulina/administração & dosagem , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Recidiva , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Adulto JovemRESUMO
OBJECTIVE: Sulfonylureas are first-line treatment of hepatocyte nuclear factor 1-α (HNF1A) diabetes (maturity-onset diabetes of the young type 3), but many patients do not achieve optimal glycemic control without episodes of hypoglycemia. We investigated the combination of the sulfonylurea glimepiride and the dipeptidyl peptidase 4 inhibitor linagliptin versus glimepiride monotherapy with respect to glycemic variability, glycemic control, and risk of hypoglycemia. RESEARCH DESIGN AND METHODS: In a randomized, double-blinded, crossover trial, patients with HNF1A diabetes (n = 19; mean ± SD age 43 ± 14 years, BMI 24.8 ± 2.8 kg/m2, and glycated hemoglobin [HbA1c] 7.4 ± 0.2% [57.1 ± 7.3 mmol/mol]) were randomly assigned to treatment with glimepiride + linagliptin 5 mg (16 weeks), washout (4 weeks), and glimepiride + placebo (16 weeks) (or vice versa). Glimepiride was titrated targeting a fasting plasma glucose of 4.5-6.0 mmol/L without hypoglycemia. Treatments were evaluated by continuous glucose monitoring (CGM), HbA1c, and meal test. RESULTS: Compared with glimepiride + placebo, glimepiride + linagliptin did not significantly improve the primary end point, mean amplitude of glycemic excursions (MAGE) (mean difference -0.7 mmol/L, P = 0.1540), but displayed significant reductions in coefficient of variation on CGM (-3.6%, P = 0.0401), HbA1c (-0.5%, P = 0.0048), and glimepiride dose (-0.7 mg/day, P = 0.0099). ß-cell glucose sensitivity (assessed as C-peptide-to-glucose ratio) during meal test improved with glimepiride + linagliptin. Incidences of hypoglycemia were similar with both treatments. CONCLUSIONS: Linagliptin as add-on treatment to glimepiride improved glycemic variability and control without increasing risk of hypoglycemia in patients with HNF1A diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Linagliptina/administração & dosagem , Linagliptina/efeitos adversos , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Automonitorização da Glicemia , Estudos Cross-Over , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: Heterozygous mutations in the insulin gene that affect proinsulin biosynthesis and folding are associated with a spectrum of diabetes phenotypes, from permanent neonatal diabetes to MODY. In vivo studies of these mutations may lead to a better understanding of insulin mutation-associated diabetes and point to the best treatment strategy. We studied an 18-year-old woman with MODY heterozygous for the insulin mutation p.R46Q (GlnB22-insulin), measuring the secretion of mutant and wild-type insulin by LC-MS. The clinical study was combined with in vitro studies of the synthesis and secretion of p.R46Q-insulin in rat INS-1 insulinoma cells. METHODS: We performed a standard 75 g OGTT in the 18-year-old woman and measured plasma glucose and serum insulin (wild-type insulin and GlnB22-insulin), C-peptide, proinsulin, glucagon and amylin. The affinity of GlnB22-insulin was tested on human insulin receptors expressed in baby hamster kidney (BHK) cells. We also examined the subcellular localisation, secretion and impact on cellular stress markers of p.R46Q-insulin in INS-1 cells. RESULTS: Plasma GlnB22-insulin concentrations were 1.5 times higher than wild-type insulin at all time points during the OGTT. The insulin-receptor affinity of GlnB22-insulin was 57% of that of wild-type insulin. Expression of p.R46Q-insulin in INS-1 cells was associated with decreased insulin secretion, but not induction of endoplasmic reticulum stress. CONCLUSIONS/INTERPRETATION: The results show that beta cells can process and secrete GlnB22-insulin both in vivo and in vitro. Our combined approach of immunoprecipitation and LC-MS to measure mutant and wild-type insulin may be useful for the study of other mutant insulin proteins. The ability to process and secrete a mutant protein may predict a more benign course of insulin mutation-related diabetes. Diabetes develops when the beta cell is stressed because of increased demand for insulin, as observed in individuals with other insulin mutations that affect the processing of proinsulin to insulin or mutations that reduce the affinity for the insulin receptor.
Assuntos
Diabetes Mellitus/genética , Insulina/genética , Adolescente , Animais , Western Blotting , Peptídeo C/metabolismo , Linhagem Celular , Cricetinae , Feminino , Glucagon/metabolismo , Humanos , Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Proinsulina/metabolismo , Ratos , Receptor de Insulina/metabolismoRESUMO
OBJECTIVE: Increasing parity may be a risk factor for the development of type 2 diabetes mellitus and the metabolic alterations during a normal pregnancy induces a prediabetic state; thus, multiple pregnancies may act as a risk factor for development of type 2 diabetes if these physiological alterations in glucose homeostasis are not reversed postpartum. We hypothesize that multiple pregnancies may lead to ß-cell exhaustion and that the insulin resistance that occurs during pregnancy may persist after multiple births. RESEARCH DESIGN AND MEASURES: A total of 28 healthy premenopausal women were recruited: 15 high parity women (≥4 children) and 13 body mass index (BMI)-matched and age-matched low parity women (1 and 2 children). The study consisted of an intravenous glucose tolerance test for assessment of ß-cell function followed by a hyperinsulinemic euglycemic clamp for assessment of insulin sensitivity. Dual-energy X-ray absorptiometry was performed to assess body composition. RESULTS: All anthropometric measures, measures of body composition and baseline blood samples were comparable between the 2 groups. Neither first phase insulin release (0-10â min, p=0.92) nor second phase insulin release (10-60â min, p=0.62), both measured as area under the curve, differed between the 2 groups. The M-value, calculated as the mean glucose infusion rate during the last 30â min of the clamp period, was 8.66 (7.70 to 9.63) mg/kg/min in the high parity group compared with 8.41 (7.43 to 9.39) mg/kg/min in the low parity group (p=0.69). CONCLUSIONS: We did not detect any effects of increasing parity on insulin sensitivity or ß-cell function.
RESUMO
BACKGROUND: CD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability to recognize and interact with extracellular lipids. We tested whether this specific polymorphism results in abnormal lipid accumulation in skeletal muscle and liver and other indices of metabolic dysfunction. METHODS: 40 healthy men with a mean age of 55â years were characterized metabolically including assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) and intramyocellular lipid content (IMCL) by MR spectroscopy, and ß-cell function by an intravenous glucose tolerance test. Changes in insulin signaling and CD300LG mRNA expression were determined by western blotting and quantitative PCR in muscle and adipose tissue. RESULTS: Compared with the 20 controls (CC carriers), the 20 CT carriers (polymorphism carriers) had higher IMCL (p=0.045), a reduced fasting forearm glucose uptake (p=0.011), a trend toward lower M-values during the clamp; 6.0â mg/kg/min vs 7.1 (p=0.10), and higher IHLC (p=0.10). CT carriers had lower CD300LG mRNA expression and CD300LG expression in muscle correlated with IMCL (ß=-0.35, p=0.046), forearm glucose uptake (ß=0.37, p=0.03), and tended to correlate with the M-value (ß=0.33, p=0.06), independently of CD300LG genotype. ß-cell function was unaffected. CONCLUSIONS: The CD300LG polymorphism was associated with decreased CD300LG mRNA expression in muscle and adipose tissue, increased IMCL, and abnormalities of glucose metabolism. CD300LG mRNA levels correlated with IMCL and forearm glucose uptake. These findings link a specific CD300LG polymorphism with features of the metabolic syndrome suggesting a role for CD300LG in the regulation of common metabolic traits. TRIAL REGISTRATION NUMBER: NCT01571609.